ミオクロニー脱力発作を伴うてんかん

Lafora disease (LD) is a fatal neurodegenerative disorder caused by mutations in the EPM2A or EPM2B/NHLRC1 genes, encoding Laforin and Malin, respectively. While the Laforin/Malin E3-ubiquitin ligase complex is a known regulator of canonical autophagy and glycogen metabolism, its role in non-canonical autophagy pathways remains unexplored. Given that neuroinflammation is a hallmark of LD, we investigated the relationship between the Laforin/Malin complex and Rubicon, a critical regulator of LC3-associated phagocytosis (LAP) and LC3-associated endocytosis (LANDO). In this work, we identify Rubicon as a novel substrate and binding partner of the Laforin/Malin complex. Co-immunoprecipitation and confocal microscopy assays in HEK293 and U2OS cells demonstrated that Malin physically interacts with Rubicon, promoting its K63-linked polyubiquitination. This post-translational modification adds another layer of control to the regulation of Rubicon in specific cellular contexts. To determine the functional relevance of this interaction in LD, we assessed LAP and LANDO in primary astrocytes from Malin-deficient mice. Using flow cytometry, we quantified the engulfment and degradation of Zymosan particles and microglial debris (LAP), as well as EGF receptor internalization (LANDO). Surprisingly, no significant functional impairments were observed in Malin-deficient astrocytes compared to WT controls. These findings suggest that while the Laforin/Malin complex regulates Rubicon via K63-linked ubiquitination, redundant signaling nodes may preserve non-canonical autophagy output in Malin-deficient astrocytes.

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by SCN1A haploinsufficiency. While brain pathology has been extensively studied, the retina remains underexplored. This study investigated retinal structural, functional, vascular, and cellular changes in a Scn1a+/- rat model of DS. Anatomical quantification revealed thinning of the retinal nerve fiber layer and thickening of the outer plexiform layer. Electroretinography (ERG) showed selectively reduced oscillatory potential amplitudes, suggesting dysfunction of neurovascular coupling. Consistent with these findings, immunohistochemistry demonstrated aberrant vascular morphology, including increased vessel curvature and reduced branching density. In addition, we observed robust microglial activation in the outer and inner plexiform layers; however, astrocyte morphology remained largely unchanged. Fenfluramine, an approved anti-seizure drug for DS, attenuated microglial activation but failed to rescue retinal structural or vascular deficits, indicating a dissociation between its anti-inflammatory and disease-modifying effects. Our findings suggest that multimodal retinal assessment could serve as a noninvasive biomarker platform for monitoring disease progression and therapeutic response in DS.

Lance-Adams syndrome is a severe and disabling posthypoxic myoclonus in humans. Its underlying mechanisms are still unknown. We aimed to develop a new animal model of Lance-Adams syndrome. We performed our procedures on Sprague-Dawley rats monitored for basic cardiorespiratory parameters. The Group 1 was sedated and submitted to hypoxia in a dedicated cage where oxygen was replaced with nitrogen. The Groups 2 and 3 were sedated, intubated, ventilated, and submitted to anoxia with the replacement of oxygen by nitrogen in the ventilatory circuit, either continuously (Group 2) or intermittently (Group 3). Rats benefited from cardiopulmonary resuscitation. Each rat was evaluated daily for spontaneous, wandering-induced, and auditory stimuli-induced myoclonic jerks, for the latter using a quantitative myoclonus score. In the Group 1 (n = 19), the duration of hypoxia was 25 ± 20 min for the surviving animals (n = 14/19) and minimal partial pressure of oxygen in the cage was 7.2 ± 0.8%. In the Group 2 (n = 38), the duration of anoxia was 5.6 ± 1.9 min for the surviving animals (n = 23/38). In the Group 3 (n = 30), the total duration of anoxia was 15 ± 3.5 min in the surviving animals (n = 15/30). These three procedures did not allow for generating a myoclonic phenotype. Some refinements of hypoxic/anoxic procedures are still needed to develop an animal model of posthypoxic myoclonus that would be a precious tool to understand better the pathophysiology of Lance-Adams syndrome.

BACKGROUND: Epilepsy is a core feature of Angelman syndrome (AS) and a major contributor to morbidity and caregiver burden. The current study provides updated caregiver-reported data on seizure characteristics, triggers, and management in AS. METHODS: Caregivers of 130 individuals with AS enrolled in the Linking Angelman and Dup15q Data for Expanded Research Database completed an online questionnaire assessing seizure characteristics, age at first seizure and diagnosis, perceived triggers, and management strategies. Participants were grouped by molecular subtype (deletion vs nondeletion). Descriptive statistics and group comparisons were conducted. RESULTS: Seizures were more frequently reported in individuals with deletion subtypes compared to those with nondeletion subtypes. The most common seizure-related manifestations (myoclonic, atonic, and atypical absence features) did not differ between groups. Individuals with deletion subtypes experienced earlier epilepsy diagnosis than those with nondeletion subtypes, though age at first seizure prompting medical attention did not differ significantly between the groups. About half of caregivers were unsure of seizure triggers; among identified triggers, illness or infection with a fever was most common. Pharmacologic treatment was the primary management approach, with levetiracetam most frequently reported. Side effects were the most common reason for medication discontinuation, and only 69% of caregivers reported access to or use of an acute seizure rescue medication. CONCLUSIONS: Caregiver-reported data from the Linking Angelman and Dup15q Data for Expanded Research Database provide an updated characterization of seizures in AS. Gaps in trigger identification and availability or use of rescue medications highlight opportunities to improve standard-of-care implementation in AS.

Late-onset epileptic spasms (LOES) are epileptic spasms (ES) commencing after age 12 months, often misdiagnosed and having uncertain relationship to infantile spasms. Previous studies of mostly small LOES cohorts frequently reported 'cryptogenic' aetiologies. We studied the presentations, aetiologies, treatment responses and outcomes in a large LOES cohort, evaluated with modern neuroimaging and genomic testing. In this retrospective cohort study, 62 children with video-confirmed epileptic spasms, diagnosed between 2011 and 2021, were included. All had epileptiform activity on EEG, but none had hypsarrhythmia. Median age at epileptic spasms onset was 23 months (range 1-15 years) and median delay to diagnosis was 8 months (interquartile range: 3-15). Only 24% children were correctly diagnosed at presentation, common misdiagnoses being myoclonic epilepsies and non-epileptic phenomenon. Aetiology was identified in 95%. Structural-malformative aetiologies were present in 63% (most commonly focal cortical dysplasia and mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy). Other aetiologies were structural-acquired in 13% (mostly postnatal stroke and CNS infections), genetic in 13% (mostly intragenic variants and chromosomopathies) and oncological in 6% (history of leukaemia, two with CNS involvement). Children with structural aetiologies often had normal development prior to onset of epileptic spasms, a later median age of epileptic spasms onset and were more likely to have asymmetric or subtle epileptic spasms and additional seizures prior to epileptic spasms. Epileptic spasms ceased in 29% children treated with prednisolone, most having genetic aetiologies and in 35% treated with vigabatrin, all having structural-malformative aetiologies. Apart from clobazam, which was effective in 17% of children, all other antiseizure medications, vagus nerve stimulation and ketogenic diet therapy were ineffective. Epileptic spasms ceased in 86% (18/21) of children who underwent epilepsy surgery. At median follow-up of 10.3 years, 53% children were free of all seizures and 76% were free of epileptic spasms. More children with unilateral structural-malformative aetiologies achieved seizure freedom than other aetiologies, most commonly following surgery but occasionally following treatment with vigabatrin or clobazam. Impairment of cognitive function or adaptive behaviour (formally assessed in 90%) was significantly more common in children with genetic than structural aetiologies, and in children with ongoing seizures than seizure freedom. Among children who underwent epilepsy surgery, 62% achieved average or low-average adaptive functioning or normal intellectual capacity. This study highlights the importance of prompt recognition of epileptic spasms in older children for improved seizure and developmental outcomes. Brain malformations and insults are the predominant causes of LOES, and when unilateral, respond best to epilepsy surgery.